EP3222614A2 - Composé de biguanide et utilisation de celui-ci - Google Patents

Composé de biguanide et utilisation de celui-ci Download PDF

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Publication number
EP3222614A2
EP3222614A2 EP15860894.3A EP15860894A EP3222614A2 EP 3222614 A2 EP3222614 A2 EP 3222614A2 EP 15860894 A EP15860894 A EP 15860894A EP 3222614 A2 EP3222614 A2 EP 3222614A2
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European Patent Office
Prior art keywords
biguanide
methyl
piperidin
phenyl
cancer
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EP15860894.3A
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German (de)
English (en)
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EP3222614B1 (fr
EP3222614A4 (fr
Inventor
Hong Woo Kim
Jae Kap Jeong
Ji Sun Lee
Hye Jin Heo
Hong Bum Lee
Ji Ae KOOK
Sung Wuk Kim
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Immunomet Therapeutics Inc
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Immunomet Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a guanidine compound and a use thereof, and more specifically, to a guanidine derivative showing excellent effects of inhibiting cancer cell proliferation, cancer metastasis, and cancer recurrence; a preparation method thereof; and a pharmaceutical composition containing the same as an active ingredient.
  • cancer cells While normal cells produce ATP via oxidative phosphorylation and rarely produce lactic acid, cancer cells produce ATP via glycolysis and lactic acid fermentation. Accordingly, unlike normal cells, cancer cells require a higher amount of glucose, and glucose is converted by a pro-oncogenic metabolism which prefers glycolysis even in an aerobic environment (Warburg effect). Cancer cells utilize such a metabolic pathway as a major source of energy supply for producing energy sources, and as such, cancer cells create an environment in which survival, proliferation, angiogenesis, and metastasis can occur actively, and progress into a malignant tumor.
  • the biguanide-based drugs such as phenformin and metformin are known as mitochondrial complex 1 inhibitor, and these drugs are known to inhibit differentiation and survival of cancer cells by increasing the energy stress of the cancer cells via inhibition of their oxidative phosphorylation.
  • the efficacies of these drugs are not strong enough and thus it is difficult for them to be developed into anticancer drugs.
  • phenformin a biguanide-based drug
  • its use has been fully prohibited since the late 1970s due to the side-effect of severe lactic acidosis. Accordingly, there is a need to develop a biguanide-based material with improved physicochemical properties exhibiting excellent pharmacological actions compared to the existing metformin while not exhibiting any side-effects, as in phenformin.
  • the present invention provides a novel guanidine derivative or a pharmaceutically acceptable salt thereof which exhibits excellent effects of inhibiting cancer cell proliferation, cancer metastasis, and cancer recurrence even with small doses compared to existing drugs, and a preparation method thereof.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer containing the above compound or a pharmaceutically acceptable salt thereof as an active ingredient, and specifically, the cancer may be a disease selected from the group consisting of uterine cancer, breast cancer, stomach cancer, brain cancer, rectal cancer, colorectal cancer, lung cancer, skin cancer, blood cancer, and liver cancer.
  • An object of the present invention provides a novel guanidine derivative compound or a pharmaceutically acceptable salt thereof selected from the group consisting of Compounds 1) to 165) described below.
  • Another object of the present invention provides a pharmaceutical composition for preventing or treating cancer containing the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Still another object of the present invention provides a use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating cancer.
  • Still another object of the present invention provides a method for preventing or treating cancer including administering a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the guanidine derivative according to the present invention shows excellent effects of inhibiting cancer cell proliferation, cancer metastasis, and cancer recurrence even with small doses, and may thus be effectively used in treating various cancers such as uterine cancer, breast cancer, stomach cancer, brain cancer, rectal cancer, colorectal cancer, lung cancer, skin cancer, blood cancer, liver cancer, etc. , inhibiting cancer cell proliferation and cancer metastasis.
  • the present invention provides a novel guanidine derivative compound selected from the group consisting of the following Compounds 1) to 165) and a pharmaceutically acceptable salt thereof:
  • the N1,N1-dimethyl-N5-piperidine biguanide compound according to the present invention may be prepared by an illustrative method shown in Reaction Scheme 1 below. Furthermore, among the compounds according to the present invention, the compounds with a biguanide structure having substituents at N1 and N5 may be prepared by a method varying only the cyanoguanidine and amine compounds in Reaction Scheme 1 below.
  • N1-butyl-N2-cycloheptyl biguanide hydrochloride compound according to the present invention may be prepared by an illustrative method shown in Reaction Scheme 2 below. Furthermore, among the compounds according to the present invention, the compounds with a biguanide structure having substituents at N1 and N2 may be prepared by a method varying only the thiourea and guanidine compounds in Reaction Scheme 2 below.
  • the thiourea compound was dissolved in ethanol and then 3 equivalents of guanidine hydrochloride and 2 equivalents of mercury oxide were added thereto and the mixture was stirred under reflux for 1 hour. Once the reaction is completed, a compound can be obtained by filtration, evaporation of the solvent under reduced pressure and purification.
  • the N1-methyl biguanide hydrochloride compound according to the present invention may be prepared by an illustrative method shown in Reaction Scheme 3 below. Furthermore, among the compounds according to the present invention, the biguanide compounds having a substituent at N1may be prepared by a method varying only the amine compound in Reaction Scheme 3 below.
  • the amine compound was dissolved in n -butanol and then 1 equivalent of the cyanoguanidine compound and 1 equivalent of concentrated hydrochloric acid were added thereto and the mixture was stirred under reflux for 15 hours. Once the reaction is completed, a compound can be obtained by solvent evaporation under reduced pressure and purification.
  • N-(6,6-dimethyl-4-oxo-1,4,5,6-tetrahydropyrimidin-2-yl)piperidin-1-carboximidamide hydrochloride compound according to the present invention may be prepared by an illustrative method shown in Reaction Scheme 4 below.
  • the guanide compounds having a structure of tetrahydropyrimidine may be prepared by a method varying only the cyanoguanidine and amine compounds in Reaction Scheme 3 below.
  • the aminobutanoate compound was dissolved in ethanol and then 1 equivalent of the cyanoguanidine compound was added thereto and the mixture was stirred under reflux for 15 hours. Once the reaction is completed, a compound can be obtained by solvent evaporation under reduced pressure and purification.
  • the pharmaceutically acceptable salt of the above compounds according to the present invention may be an acid addition salt formed using an organic or inorganic acid.
  • the organic acid may include formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid, maleic acid, malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, dichloroacetic acid, aminooxyacetic acid, benzenesulfonic acid, 4-toluenesulfonic acid, and methanesulfonic acid.
  • Examples of the inorganic acid may include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, and boric acid.
  • the acid addition salt mentioned above may be prepared by applying to the conventional methods of salt preparation, for example, by a) directly mixing the compound above with an acid, b) mixing any of these by dissolving in a solvent or water-containing solvent, or c) mixing the compound above with an acid in the presence of a solvent or hydrated solvent.
  • the pharmaceutically acceptable salt of the compound may be a salt with an acid selected from the group consisting of formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid, maleic acid, malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxyacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, and boric acid.
  • an acid selected from the group consisting of formic acid, acetic acid, propionic acid,
  • Another aspect of the present invention provides a pharmaceutical composition containing the guanidine derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition according to the present invention has an excellent effect of inhibiting the proliferation of cancer cells and can thus be used for preventing or treating various cancers. Accordingly, the present invention provides a use of the guanidine derivative compound or a pharmaceutically acceptable salt thereof for preventing or treating cancer, and a method for preventing or treating cancer including administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the cancer may include uterine cancer, breast cancer, stomach cancer, brain cancer, rectal cancer, colorectal cancer, lung cancer, skin cancer, blood cancer, and liver cancer, but is not limited thereto.
  • the pharmaceutical composition of the present invention may include at least one pharmaceutically acceptable carrier, in addition to active ingredients.
  • pharmaceutically acceptable carrier refers to a pharmaceutical excipient, which is useful in formulating pharmaceutically active compounds for administration and known as substantially non-toxic and non-sensitive under the conditions of use. The exact ratio of the excipient may be determined not only by the solubility, chemical properties, selected routes of administration of an active compound, but also by the standard pharmaceutical practices.
  • the pharmaceutical composition of the present invention may be formulated into a form suitable for the desired administration method, using additives such as an appropriate and physiologically acceptable excipient, disintegrant, sweetener, binder, coating agent, swelling agent, lubricant, glidant, flavoring agent, etc.
  • additives such as an appropriate and physiologically acceptable excipient, disintegrant, sweetener, binder, coating agent, swelling agent, lubricant, glidant, flavoring agent, etc.
  • the pharmaceutical composition may be formulated into tablets, capsules, pills, granules, powders, injections, and liquids, but is not limited thereto.
  • compositions of the pharmaceutical composition and pharmaceutically acceptable carriers may be appropriately selected according to the technologies known in the art.
  • the term "subject” refers to a warm-blooded animal such as a mammal which has a particular disease, disorder, or illness, for example, humans, orangutans, chimpanzees, mice, rats, dogs, cows, chickens, pigs, goats, sheep, etc. , but the animal is not limited thereto.
  • treatment refers to any action to alleviate symptoms, to temporarily or permanently eliminate the cause(s) of symptoms, and to prevent or delay the occurrence of symptoms and the progress of the diseases, disorders, and illnesses described above, but is not limited thereto.
  • the term "effective amount" of an active ingredient of the pharmaceutical composition of the present invention refers to the amount required for achieving the treatment of a given disease. Accordingly, the effective amount may be adjusted according to various factors including the type of a disease, severity of illness, and kinds and amounts of active ingredients and other ingredients contained in a composition, formulation type, age, weight, general health conditions, sex, and diets of a patient, duration and route of administration, release rate of a composition, duration of treatment, and drugs used in combination.
  • the compound or a pharmaceutically acceptable salts thereof according to the present invention may be administered once or a few times daily, in an amount of a total of 50 mg/kg to 3000 mg/kg.
  • the amount for administration may vary according to various factors illustrated above, and may be administered in a lesser amount or a higher amount compared to the above range of the amount for administration depending on the cases.
  • the target compound was obtained as a white solid (1.28 g, 47.0%) in the same manner as in Example 1, except that piperidine cyanoguanidine was used instead of N , N- dimethylcyano guanidine.
  • 1 H NMR 600 MHz, DMSO
  • 1.62 m, 8H
  • 1.47 m, 4H
  • LCMS 238.0 [M+H] +
  • the target compound was obtained as a white solid (0.62 g, 70.7%) in the same manner as in Example 1, except that N- methyl-1-(naphthalen-1-yl)methanamine was used instead of piperidine.
  • 1 H NMR 600 MHz, DMSO
  • LCMS 284.0 [M+H] +
  • the target compound was obtained as a white solid (1.8 g, 60.0%) in the same manner as in Example 1, except that benzo[d][1,3]dioxol-5-yl methanamine was used instead of piperidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 7.06 s, 1H
  • 6.90 s, 2H
  • 5.99 s, 2H
  • 3.87 s, 2H
  • LCMS 264.0 [M+H] +
  • the target compound was obtained as a white solid (0.65 g, 50.0%) in the same manner as in Example 1, except that piperidine cyanoguanidine and pyrrolidine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 3.07 (m, 2H), 2.97 (t, J 6 Hz, 6H), 1.83 (m, 2H), 1.69 (m, 6H), 1.54 (m, 2H)
  • the target compound was obtained as a white solid (0.11 g, 15.0%) in the same manner as in Example 1, except that isopropylcyanoguanidine and 1-(pyridin-3-yl)methanamine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 8.52 s, 1H
  • 8.46 m, 1H
  • 7.72 m, 1H
  • LCMS 235.1 [M+H] +
  • the target compound was obtained as a white solid (0.52 g, 30.2%) in the same manner as in Example 1, except that N,N- diisopropylcyanoguanidine and N- ethylpropan-1-amine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • 2.77 (m, 4H) 1.57 (m, 6H), 1.15 (m, 6H), 0.87 (m, 6H)
  • LCMS 256.1 [M+H] +
  • the target compound was obtained as a white solid (0.60 g, 31.0%) in the same manner as in Example 1, except that N,N- dipropylcyanoguanidine was used instead of N,N- dimethylcyano guanidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 3.22 m, 8H
  • 1.53 m, 8H
  • 0.91 m, 8H
  • LCMS 254.1 [M+H] +
  • the target compound was obtained as a white solid (1.00 g, 40.0%) in the same manner as in Example 1, except that piperidine cyanoguanidine and benzo[d][1,3]dioxol-5-ylmethanamine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 7.04 s, 1H
  • 6.93 s, 2H
  • 3.33 (m, 4H) 1.62 (m, 4H), 1.47 (m, 2H)
  • LCMS 304.1 [M+H] +
  • the target compound was obtained as a white solid (0.56 g, 57.0%) in the same manner as in Example 1, except that 4-chlorophenylcyanoguanidine and N- benzyl-2-methylpropan-2-amine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 7.66 m, 4H
  • 7.38 m, 5H
  • LCMS 358.1 [M+H] +
  • the target compound was obtained as a white solid (0.58 g, 26.0%) in the same manner as in Example 1, except that 3-bromophenyl cyanoguanidine and 3-bromoaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • LCMS 411.1 [M+H] +
  • the target compound was obtained as a white solid (0.43 g, 41.3%) in the same manner as in Example 1, except that piperidine cyanoguanidine and 2-chlorobenzylamine were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 7.60 m, 1H
  • 7.42 m, 1H
  • 7.25 m, 2H
  • 1.52 m, 2H
  • the target compound was obtained as a white solid (0.42 g, 36.8%) in the same manner as in Example 1, except that piperidine cyanoguanidine and 4-chlorophenethylamine were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, CD 3 OD
  • ⁇ 7.40 m, 2H
  • 3.01 m, 8H
  • 1.70 m, 4H
  • LCMS 308.1 [M+H] +
  • the target compound was obtained as a white solid (0.42 g, 36.8%) in the same manner as in Example 1, except that piperidine cyanoguanidine and 2-chlorophenethylamine were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, CD 3 OD
  • ⁇ 7.38 m, 2H
  • 3.03 m, 8H
  • 1.68 m, 4H
  • the target compound was obtained as a white solid (0.27 g, 21.1%) in the same manner as in Example 1, except that N,N- propylcyanoguanidine and dicyclohexylamine were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 2.55 m, 6H
  • 1.49 m, 20H
  • 1.44 m, 4H
  • LCMS 350.1 [M+H] +
  • the target compound was obtained as a white solid (0.36 g, 25.0%) in the same manner as in Example 1, except that N,N- dipropylcyanoguanidine and dipropylamine were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 3.30 m, 8H
  • 1.48 m, 8H
  • 0.80 m, 12H
  • the target compound was obtained as a white solid (3.00 g, 45.0%) in the same manner as in Example 1, except that isopropylcyanoguanidine and 2-chloroaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • 2.97 m, 1H
  • the target compound was obtained as a white solid (0.29 g, 40.0%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 4-trifluoromethyl benzylamine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • LCMS 343.2 [M+H] +
  • the target compound was obtained as a white solid (0.18 g, 10.0%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 4-trifluoromethylaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 7.64 m, 4H
  • 3.30 m, 4H
  • 2.25 m, 4H
  • the target compound was obtained as a white solid (0.15 g, 23.0%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 3-trifluoromethylbenzylamine were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 7.62 m, 4H
  • the target compound was obtained as a white solid (0.51 g, 52.0%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 3-trifluoromethylaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 7.82 s, 1H
  • LCMS 329.2 [M+H] +
  • the target compound was obtained as a white solid (0.10 g, 15.5%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 3-trifluoromethoxyaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • the target compound was obtained as a white solid (0.04 g, 47.0%) in the same manner as in Example 1, except that 4-ethoxypiperidine cyanoguanidine and 3-trifluoromethylaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 7.64 m, 4H
  • 3.70 m, 3H
  • 3.48 m, 2H
  • LCMS 358.2 [M+H] +
  • the target compound was obtained as a white solid (0.12 g, 60.6%) in the same manner as in Example 1, except that 4-ethoxypiperidine cyanoguanidine and 3-trifluoromethylaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • the target compound was obtained as a white solid (0.10 g, 48.3%) in the same manner as in Example 1, except that 4-ethoxypiperidine cyanoguanidine and 3-trifluoromethoxyaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • the target compound was obtained as a white solid (0.09 g, 44.7%) in the same manner as in Example 1, except that 4-ethoxypiperidine cyanoguanidine and 4-trifluoromethylaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • LCMS 374.2 [M+H] +
  • the target compound was obtained as a white solid (0.09 g, 27.0%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 4-chloroaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 7.39 m, 4H
  • 3.45 m, 4H
  • 2.34 m, 4H
  • LCMS 295.2 [M+H] +
  • the target compound was obtained as a white solid (0.12 g, 44.3%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 3-fluoroaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • 7.31 m, 1H
  • 3.34 m, 4H
  • the target compound was obtained as a white solid (0.02 g, 6.0%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 3-fluoroaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 7.29 m, 1H
  • 7.09 m, 1H
  • 7.02 m, 1H
  • 6.89 m, 1H
  • the target compound was obtained as a white solid (0.04 g, 1.0%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 2-chloroaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.43 m, 1H
  • 7.25 m, 1H
  • 7.08 m, 1H
  • 6.98 m, 1H
  • the target compound was obtained as a white solid (0.02 g, 7.0%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 4-chlorobenzylamine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • LCMS 309.4 [M+H] +
  • the target compound was obtained as a white solid (0.02 g, 6.0%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 2-chlorobenzylamine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.42 m, 2H
  • 7.31 m, 2H
  • 4.52 s, 2H
  • LCMS 309.4 [M+H] +
  • the target compound was obtained as a white solid (0.10 g, 36.1%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 4-fluoroaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, DMSO-d 6 ) ⁇ 7.76 (s, 1H), 7.37 (m, 1H), 7.12 (t, 1H), 7.02 (s, 1H) 3.46 (m, 4H), 2.33 (m, 4H), 2.19 (s, 3H) LCMS: 279.4 [M+H] +
  • the target compound was obtained as a white solid (0.10 g, 35.9%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 2-fluoroaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, DMSO-d 6 ) ⁇ 7.75 (s, 1H), 7.15 (m, 2H), 7.13 (s, 1H), 3.43 (s, 4H), 2.38 (s, 4H), 2.19 (s, 3H)
  • the target compound was obtained as a white solid (0.03 g, 0.8%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 3-chlorobenzylamine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • LCMS 309.4 [M+H] +
  • the target compound was obtained as a white solid (0.22 g, 41.0%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 1-butylamine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 4.29 m, 2H
  • 3.71 s, 4H
  • 3.50 m, 3H
  • the target compound was obtained as a white solid (0.06 g, 12.0%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 3,4-dichloroaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • LCMS 329.1, 331.1 [M, M+2] +
  • the target compound was obtained as a white solid (0.06 g, 18.0%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 3,4-difluoroaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.43 m, 1H
  • 7.22 q, 1H
  • 7.07 m, 1H
  • LCMS 297.2 [M+H] +
  • the target compound was obtained as a white solid (0.49 g, 13.0%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 3,5-difluoroaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • LCMS 297.2 [M+H] +
  • the target compound was obtained as a white solid (0.12 g, 40.0%) in the same manner as in Example 1, except that 4-methylpiperazinecyanoguanidine and 3,4,5-trifluoroaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.20 m, 2H
  • 3.58 m, 4H
  • 2.52 m, 4H
  • LCMS 315.2 [M+H] +
  • the target compound was obtained as a white solid (0.25 g, 43.0%) in the same manner as in Example 1, except that 3-pyridinecyanoguanidine and 3-trifluoroaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 8.56 m, 2H
  • 8.33 s, 1H
  • 7.85 d, 1H
  • 7.67 s, 1H
  • LCMS 323.2 [M+H] +
  • the target compound was obtained as a white solid (0.20 g, 37.0%) in the same manner as in Example 1, except that 3-pyridinecyanoguanidine and 4-trifluoromethoxybenzylamine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 8.48 s, 1H
  • 8.00 d, 1H
  • 7.82 s, 1H
  • 7.75 s, 1H
  • the target compound was obtained as a white solid (0.05 g, 8.0%) in the same manner as in Example 1, except that 3-pyridinecyanoguanidine and 3-trifluoromethylbenzylamine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • LCMS 337.2 [M+H] +
  • the target compound was obtained as a white solid (0.05 g, 14.6%) in the same manner as in Example 1, except that 3-methylpiperidinecyanoguanidine and cyclopentylamine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 400 Hz, CD 3 OD
  • ⁇ 4.05 m, 4H
  • 2.96 m, 1H
  • 2.68 m, 1H
  • 1.98 m, 3H
  • the target compound was obtained as a white solid (0.03 g, 8.5%) in the same manner as in Example 1, except that 3-methylpiperidinecyanoguanidine and 4-methoxypiperidine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • the target compound was obtained as a white solid (0.04 g, 12.2%) in the same manner as in Example 1, except that 3-methylpiperidinecyanoguanidine and 4-ethoxypiperidine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 4.01 m, 2H
  • 3.82 m, 2H
  • 3.58 m, 4H
  • 2.80 m, 1H
  • LCMS 292.2 [M+H] +
  • the target compound was obtained as a white solid (0.01 g, 4.7%) in the same manner as in Example 1, except that 3-methylpiperidinecyanoguanidine and pyrazin-2-amine were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 8.48 s, 1H
  • 8.27 s, 1H
  • 8.22 s, 1H
  • 1.80 m, 4H
  • LCMS 262.1 [M+H] +
  • the target compound was obtained as a white solid (0.32 g, 49.3%) in the same manner as in Example 1, except that 4-methylpiperidinecyanoguanidine and 4-bromoaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.45 m, 2H
  • 7.30 m, 2H
  • 4.07 s, 2H
  • LCMS 338.0, 340.2 [M, M+2] +
  • the target compound was obtained as a white solid (0.49 g, 71.9%) in the same manner as in Example 1, except that 4-methylpiperidinecyanoguanidine and 3-trifluoromethoxyaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.53 s, 1H
  • 7.37 t, 1H
  • 7.26 m, 1H
  • 6.97 m, 1H
  • 1.74 (m, 2H) 1.70 (m, 1H), 1.23 (m, 2H), 1.00 (d, 3H)
  • LCMS 344.2 [M+H] +
  • the target compound was obtained as a white solid (0.50 g, 77.0%) in the same manner as in Example 1, except that 4-methylpiperidinecyanoguanidine and 3-trifluoromethylaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.84 s, 1H
  • 7.55 d, 1H
  • 7.48 t, 1H
  • 7.31 7.31
  • 3.02 (t, 2H) 1.76 (m, 2H), 1.70 (m, 1H), 1.23 (m, 2H), 0.99 (d, 3H)
  • the target compound was obtained as a white solid (0.49 g, 75.4%) in the same manner as in Example 1, except that 3-methylpiperidinecyanoguanidine and 3-trifluoromethylaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • the target compound was obtained as a white solid (0.68 g, 60.0%) in the same manner as in Example 1, except that 4-methylpiperidinecyanoguanidine and 4-trifluoromethoxyaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.45 d, 2H
  • 7.23 d, 2H
  • 4.07 d, 2H
  • LCMS 344.2 [M+H] +
  • the target compound was obtained as a white solid (0.66 g, 61.0%) in the same manner as in Example 1, except that 4-methylpiperidinecyanoguanidine and 4-trifluoromethylaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • 4H 4.06
  • s, 2H 3.04
  • t, 2H 1.76
  • m, 2H 1.70
  • LCMS 328.2 [M+H] +
  • the target compound was obtained as a white solid (0.76 g, 66.7%) in the same manner as in Example 1, except that 4-methylpiperidinecyanoguanidine and 3-trifluoromethyl-4-fluoroaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.83 d, 1H
  • 7.58 m, 1H
  • the target compound was obtained as a white solid (0.30 g, 50.3%) in the same manner as in Example 1, except that 4-methylpiperidinecyanoguanidine and 4-chloroaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 3OD
  • ⁇ 7.36 d, 2H
  • 7.31 d, 2H
  • 4.07 d, 2H
  • 1.75 m, 2H
  • LCMS 294.2 [M+H] +
  • the target compound was obtained as a white solid (0.44 g, 7.1 %) in the same manner as in Example 1, except that 4-methylpiperidinecyanoguanidine and 4-fluoroaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • the target compound was obtained as a white solid (0.29 g, 42.7%) in the same manner as in Example 1, except that 4-methylpiperidinecyanoguanidine and 3-fluoro-4-trifluoromethylaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.62 m, 2H
  • 7.24 d, 2H
  • 4.07 s, 2H
  • LCMS 346.2 [M+H] +
  • the target compound was obtained as a white solid (0.50 g, 70.1%) in the same manner as in Example 1, except that 4-methylpiperidinecyanoguanidine and 3-trifluoromethyl-4-chloroaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.95 s, 1H
  • 7.53 q, 2H
  • LCMS 362.2 [M+H] +
  • the target compound was obtained as a white solid (0.35 g, 49.7%) in the same manner as in Example 1, except that 4-methylpiperidinecyanoguanidine and 3-fluoro-4-trifluoromethoxyaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.56 d, 1H
  • 7.33 t, 1H
  • 7.15 7.15
  • LCMS 362.2 [M+H] +
  • the target compound was obtained as a white solid (0.11 g, 17.2%) in the same manner as in Example 1, except that 4-methylpiperidinecyanoguanidine and 3-trifluoromethylbenzylamine were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.63 s, 1H
  • 7.54 m, 3H
  • 4.46 s, 2H
  • 2.88 (t, 2H) 1.67 (m, 3H), 1.13 (m, 2H), 0.95 (d, 3H)
  • LCMS 342.2 [M+H] +
  • the target compound was obtained as a white solid (0.07 g, 10.8%) in the same manner as in Example 1, except that 4-methylpiperidinecyanoguanidine and 4-trifluoromethyl benzylamine were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • the target compound was obtained as a white solid (0.21 g, 30.0%) in the same manner as in Example 1, except that 3,5-dimethylpiperidinecyanoguanidine and 4-trifluoromethoxyaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, DMSO-d 6 ) ⁇ 7.77 (s, 2H), 7.49 (m, 2H), 7.30 (m, 2H), 6.98 (s, 2H), 3.95 (d, 2H), 2.48 (t, 2H), 1.77 (d, 1H), 1.64 (s, 2H), 0.88 (s, 6H), 0.87 (m, 1H)
  • LCMS 358.2 [M+H] +
  • the target compound was obtained as a white solid (0.25 g, 31.2%) in the same manner as in Example 1, except that 3,5-dimethylpiperidine cyanoguanidine and 4-trifluoromethylaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, CD 3 OD
  • ⁇ 8.90 m, 1H
  • 8.56 m, 1H
  • 8.43 m, 1H
  • 8.39 m, 1H
  • LC-MS m/z 339.2 [M+1] +
  • the target compound was obtained as a white solid (0.30 g, 29.8%) in the same manner as in Example 1, except that 3,5-dimethylpiperidinecyanoguanidine and 4-fluoroaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, DMSO-d 6 ) ⁇ 7.69 (s, 1H), 7.45 (m, 1H), 7. 39 (m, 2H), 7.32 (m, 1H), 6.95 (s, 1H), 3.95 (d, 2H), 2.40 (t, 2H), 1.68 (d, 1H), 1.62 (s, 2H), 0.88 (s, 6H), 089 (m, 1H) LCMS: 292.2 [M+H] +
  • the target compound was obtained as a white solid (0.15 g, 15.0%) in the same manner as in Example 1, except that 3,5-dimethylpiperidinecyanoguanidine and 3-trifluoromethyl-4-fluoroaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • the target compound was obtained as a white solid (0.18 g, 31.3%) in the same manner as in Example 1, except that 2,5-dihydro-1H-pyrrolecyanoguanidine and pyrazin-2-amine were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 8.57 s, 1H
  • 8.23 s, 1H
  • 7.36 s, 1H
  • the target compound was obtained as a white solid (0.40 g, 28.8%) in the same manner as in Example 1, except that 2,5-dihydro-1H-pyrrolecyanoguanidine and 2,5-dihydro-1H-pyrrole were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • the target compound was obtained as a white solid (0.59 g, 16.3%) in the same manner as in Example 1, except that 1,2,3,6-tetrahydropyridinecyanoguanidine and 1,2,3,6-tetrahydropyridine were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • LCMS 234.2 [M+H] +
  • the target compound was obtained as a white solid (0.06 g, 16.9%) in the same manner as in Example 1, except that 4-methylpiperidinecyanoguanidine and 4-aminoethylaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.37 (d, 2H), 7.25 (d, 2H), 4.09 (d, 2H), 3.2 (m, 2H), 3.01 (m, 4H), 1.75 (m, 3H), 1.21 (m, 2H), 0.98 (m, 3H)
  • LCMS 303.2 [M+H] +
  • the target compound was obtained as a white solid (0.49 g, 44.1 %) in the same manner as in Example 1, except that pyrrolidinecyanoguanidine and 4-acetylaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.95 d, 2H
  • 7.56 d, 2H
  • 3.31 d, 4H
  • the target compound was obtained as a white solid (0.93 g, 69.1 %) in the same manner as in Example 1, except that piperidinecyanoguanidine and 4-morpholin-4-ylaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.22 d, 2H
  • 6.96 d, 2H
  • 3.83 m, 4H
  • 3.12 (m, 4H) 1.69 (m, 2H)
  • LCMS 331.2 [M+H] +
  • the target compound was obtained as a white solid (0.91 g, 73.2%) in the same manner as in Example 1, except that pyrrolidinecyanoguanidine and 4-bromoaniline were used instead of N,N -dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • LCMS 310.0, 312.0 [M, M+2] +
  • the target compound was obtained as a white solid (0.31 g, 30.4%) in the same manner as in Example 1, except that piperidinecyanoguanidine and 4-methoxyaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.24 d, 2H
  • 6.91 d, 2H
  • 3.78 s, 3
  • 3.50 s, 4H
  • LCMS 276.2 [M+H] +
  • the target compound was obtained as a white solid (0.67 g, 63.6%) in the same manner as in Example 1, except that piperidinecyanoguanidine and 2-propylaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.31 m, 1H
  • 7.27 m, 1H
  • 7.21 m, 2H
  • 3.47 m, 4H
  • the target compound was obtained as a white solid (0.53 g, 44.4%) in the same manner as in Example 1, except that pyrrolidinecyanoguanidine and 2-trifluoromethylaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.70 m, 3H
  • 7.60 s, 1H
  • 3.04 d, 4H
  • LCMS 300.2 [M+H] +
  • the target compound was obtained as a white solid (0.36 g, 32.3%) in the same manner as in Example 1, except that pyrrolidinecyanoguanidine and 2-chloro-5-trifluoromethylaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.58 s, 1H
  • 7.32 m, 2H
  • 3.24 d, 4H
  • LCMS 334.2 [M+H] +
  • the target compound was obtained as a white solid (0.72 g, 54.3%) in the same manner as in Example 1, except that pyrrolidinecyanoguanidine and 3-chloro-4-fluoroaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.64 m, 1H
  • 7.29 m, 1H
  • 7.21 m, 1H
  • the target compound was obtained as a white solid (0.74 g, 60.8%) in the same manner as in Example 1, except that pyrrolidinecyanoguanidine and 2,3-dichloroaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • LCMS 300.1 [M+H] +
  • the target compound was obtained as a white solid (0.94 g, 71.2%) in the same manner as in Example 1, except that pyrrolidinecyanoguanidine and 4-trifluoromethylthioaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • LCMS 332.2 [M+H] +
  • the target compound was obtained as a white solid (0.09 g, 48.0%) in the same manner as in Example 1, except that pyrrolidinecyanoguanidine and 2,6-difluoroaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, DMSO-d 6 ) ⁇ 7.47 (s, 2H), 7.34 (m, 1H), 7.14 (t, 2H), 7.01 (s, 2H) 3.27 (d, 4H), 1.94 (d, 4H) LCMS: 268.2 [M+H] +
  • the target compound was obtained as a white solid (0.01 g, 5.0%) in the same manner as in Example 1, except that piperidinecyanoguanidine and (3-aminobenzyl)triphenylphosphonium chloride were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 7.82 (m, 6H), 7.77 (m, 3H), 7.50 (m, 6H), 7.38 (m, 2H), 7.17 (m, 1H), 4.65 (s, 2H), 3.11 (t, 4H), 1.30 (m, 4H) LCMS: 554.2 [M+H] +
  • the target compound was obtained as a white solid (1.32 g, 76.7%) in the same manner as in Example 1, except that pyrrolidinecyanoguanidine and N -methyl-4-trifluoromethoxyaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, CD 3 OD
  • LCMS 330.1 [M+H] +
  • the target compound was obtained as a white solid (0.09 g, 8.3%) in the same manner as in Example 1, except that pyrrolidinecyanoguanidine and 4-phenoxyaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 400 MHz, CD 3 OD
  • ⁇ 7.31 m, 4H
  • 7.03 m, 1H
  • 6.89 m, 4H
  • 3.43 d, 4H
  • the target compound was obtained as a white solid (0.30 g, 34.5%) in the same manner as in Example 1, except that 4-trifluoromethoxyaniline was used instead of piperidine.
  • 1 H NMR 600 MHz, DMSO
  • 3.20 s, 6H
  • LCMS 290.1 [M+H] +
  • the target compound was obtained as a white solid (0.70 g, 77.0%) in the same manner as in Example 1, except that N -methyl-4-trifluoromethoxyaniline was used instead of piperidine.
  • 1 H NMR 600 MHz, DMSO
  • 3.23 s, 6H
  • the target compound was obtained as a white solid (0.09 g, 10.0%) in the same manner as in Example 1, except that 2-(benzo[d][1,3]dioxol-5-yl)ethylcyanoguanidine and thiophenethyl were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 6.91 m, 3H
  • 6.70 m, 3H
  • 5.83 s, 2H
  • the target compound was obtained as a white solid (0.40 g, 40.6%) in the same manner as in Example 1, except that N- acetylpiperazinecyanoguanidine and 4-trifluoromethoxyaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 MHz, CD 3 OD
  • LCMS 373.1 [M+H] +
  • the target compound was obtained as a white solid (0.01 g, 22.0%) in the same manner as in Example 1, except that 2-(benzo[d][1,3]dioxol-5-yl)ethylcyanoguanidine and 1-butylamine were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 6.70 m, 3H
  • LCMS 306.2 [M+H] +
  • the target compound was obtained as a white solid (0.50 g, 28.0%) in the same manner as in Example 1, except that 2-(benzo[d][1,3]dioxol-5-yl)ethylcyanoguanidine and phenethyl were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.21 m, 5H
  • 3.13 (t, 4H) 2.99 (m, 2H), 2.87 (t, 2H)
  • LCMS 354.2 [M+H] +
  • the target compound was obtained as a white solid (0.20 g, 50.0%) in the same manner as in Example 1, except that 4,4-difluoropiperidine cyanoguanidine and 3,4-dichloroaniline were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • the target compound was obtained as a white solid (0.30 g, 60.0%) in the same manner as in Example 1, except that 4,4-difluoropiperidinecyanoguanidine and 5,6,7,8-tetrahydronaphthalen-2-amine were used instead of N,N- dimethylcyanoguanidine and piperidine.
  • the target compound was obtained as a white solid (0.15 g, 42.3%) in the same manner as in Example 92, except that 1-(1,1-dimethyl)-3-(4-fluoro)benzylthiourea and piperidineguanidine were used instead of 1-butyl-3-cycloheptylthiourea and guanidine hydrochloride.
  • 1 H NMR 600 MHz, CDCl 3 ) ⁇ 7.34 (m, 1H), 6.96 (m, 2H), 3.57 (s, 2H), 2.84 (m, 6H), 1.64 (m, 4H), 1.42 (m, 4H), 1.19 (m, 2H)
  • LCMS 306.1 [M+H] +
  • the target compound was obtained as a white solid (0.02 g, 2.0%) in the same manner as in Example 92, except that 1-phenyl-3-phenethylthiourea was used instead of 1-butyl-3-cycloheptylthiourea.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 7.32 m, 7H
  • 3.38 m, 2H
  • 2.86 (t, J 7.2 Hz, 2H)
  • LCMS 282.1 [M+H] +
  • the target compound was obtained as a white solid (0.15 g, 31.5%) in the same manner as in Example 92, except that 1-phenethyl-3-(4-bromo)phenylthiourea was used instead of 1-butyl-3-cycloheptylthiourea.
  • the target compound was obtained as a white solid (0.03 g, 2.0%) in the same manner as in Example 92, except that 1-benzyl-3-methylthiourea and N,N- dimethylguanidine were used instead of 1-butyl-3-cycloheptylthiourea and guanidine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • 7.29 (t, J 7.2 Hz, 2H)
  • LCMS 234.1 [M+H] +
  • the target compound was obtained as a white solid (0.35 g, 24.8%) in the same manner as in Example 92, except that 1-phenethyl-3-methylthiourea and N,N- dimethylguanidine were used instead of 1-butyl-3-cycloheptylthiourea and guanidine hydrochloride.
  • 1 H NMR 600 MHz, CD 3 OD
  • LCMS 248.1 [M+H] +
  • the target compound was obtained as a white solid (0.18 g, 27.0%) in the same manner as in Example 92, except that 1-(4-chloro)benzyl-3-cycloheptylthiourea was used instead of 1-butyl-3-cycloheptylthiourea.
  • 1 H NMR 400 MHz, DMSO
  • the target compound was obtained as a white solid (0.06 g, 22.0%) in the same manner as in Example 92, except that 1-piperidin-3-thiophenethylthiourea was used instead of 1-butyl-3-cycloheptylthiourea.
  • 1 H NMR 600 MHz, DMSO
  • 6.89 m, 1H
  • LCMS 280.2 [M+H] +
  • the target compound was obtained as a white solid (0.17 g, 48.0%) in the same manner as in Example 92, except that 1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-3-ethylthiourea was used instead of 1-butyl-3-cycloheptylthiourea.
  • 1 H NMR 600 Hz, CD 3 OD
  • 4.85 (s, 2H) 3.39 (t, 2H), 3.20 (q, 2H), 2.77 (t, 2H), 1.15 (t, 3H)
  • LCMS 278.1 [M+H] +
  • the target compound was obtained as a white solid (0.12 g, 30.1%) in the same manner as in Example 92, except that 1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-3-methylthiourea was used instead of 1-butyl-3-cycloheptylthiourea.
  • 1 H NMR 600 Hz, DMSO-d 6 ) ⁇ 6.79 (m, 2H), 6.64 (m, 1H), 5.91 (s, 2H), 3.24 (s, 3H), 2.66 (s, 4H) LCMS: 264.2 [M+H] +
  • the target compound was obtained as a white solid (0.58 g, 95.1%) in the same manner as in Example 92, except that 1-thiophenethyl-3-phenethylthiourea was used instead of 1-butyl-3-cycloheptylthiourea.
  • 1 H NMR 600 Hz, CD 3 OD
  • ⁇ 7.42 m, 5H
  • 6.70 m, 3H
  • 3.10 m, 4H
  • LCMS 360.1 [M+H] +
  • the target compound was obtained as a white solid (0.06 g, 26.7%) in the same manner as in Example 92, except that 1-thiophenethyl-3-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)thiourea was used instead of 1-butyl-3-cycloheptylthiourea.
  • the target compound was obtained as a white solid (0.04 g, 8.6%) in the same manner as in Example 92, except that 1-(4-trifluoromethoxy)phenyl-3-methylthiourea and pyrrolidineguanidine were used instead of 1-butyl-3-cycloheptylthiourea and guanidine hydrochloride.
  • the target compound was obtained as a white solid (0.01 g, 5.6%) in the same manner as in Example 92, except that 1-(N-methyl-4-trifluoromethoxy)phenyl-3-methylthiourea and pyrrolidineguanidine were used instead of 1-butyl-3-cycloheptylthiourea and guanidine hydrochloride.
  • the target compound was obtained as a white solid (0.65 g, 53.3%) in the same manner as in Example 92, except that 1-(benzo[d][1,3]dioxol-5-yl)methyl-3-cyclopentylthiourea was used instead of 1-butyl-3-cycloheptylthiourea.
  • 1 H NMR 600 MHz, CD 3 OD
  • ⁇ 6.93 m, 1H
  • 6.83 m, 1H
  • the target compound was obtained as a white solid (0.60 g, 23.0%) in the same manner as in Example 109, except that 1-hexylamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • 1.52 m, 2H
  • 1.31 m, 6H
  • the target compound was obtained as a white solid (0.75 g, 30.0%) in the same manner as in Example 109, except that 4-chloroaniline was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • LCMS 212.0 [M+H] +
  • the target compound was obtained as a white solid (0.52 g, 24.0%) in the same manner as in Example 109, except that 2-propenamine was used instead of methylamine hydrochloride.
  • 1 H NMR (600 MHz, DMSO) ⁇ 5.75 (m, 1H), 5.17 (d, J 16.8 Hz, 2H), 3.70 (m, 2H) LCMS: 142.2 [M+H] +
  • the target compound was obtained as a white solid (0.90 g, 18.4%) in the same manner as in Example 109, except that (benzo[d][1,3]dioxol-5-yl)methanamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • the target compound was obtained as a white solid (1.51 g, 71.4%) in the same manner as in Example 109, except that aniline was used instead of methylamine hydrochloride.
  • the target compound was obtained as a white solid (1.91 g, 53.3%) in the same manner as in Example 109, except that 1-propylamine was used instead of methylamine hydrochloride.
  • the target compound was obtained as a white solid (1.62 g, 36.6%) in the same manner as in Example 109, except that N,N- diisopropylamine was used instead of methylamine hydrochloride.
  • the target compound was obtained as a white solid (1.91 g, 74.6%) in the same manner as in Example 109, except that 4-bromoaniline was used instead of methylamine hydrochloride.
  • the target compound was obtained as a white solid (0.61 g, 27.8%) in the same manner as in Example 109, except that 4-acetylaniline was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • 2.50 s, 3H
  • LCMS 220.2 [M+H] +
  • the target compound was obtained as a white solid (1.36 g, 79.5%) in the same manner as in Example 109, except that morpholin-4-yl was used instead of methylamine hydrochloride.
  • the target compound was obtained as a white solid (0.05 g, 2.0%) in the same manner as in Example 109, except that 2-trifluoromethylaniline was used instead of methylamine hydrochloride.
  • 1 H NMR 400 MHz, DMSO
  • 8.03 (d, J 8 Hz, 1H)
  • 7.53 (t, J 8 Hz, 2H)
  • 7.79 (d, J 8 Hz, 1H)
  • the target compound was obtained as a white solid (1.85 g, 89.3%) in the same manner as in Example 109, except that 4-methoxyaniline was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • 3.70 s, 3H
  • LCMS 208.1 [M+H] +
  • the target compound was obtained as a white solid (0.75 g, 25.0%) in the same manner as in Example 109, except that 2-propylaniline was used instead of methylamine hydrochloride.
  • the target compound was obtained as a white solid (0.96 g, 36.6%) in the same manner as in Example 109, except that 4-morpholin-4-ylaniline was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • 3.71 m, 4H
  • 3.03 m, 4H
  • the target compound was obtained as a white solid (0.20 g, 8.0%) in the same manner as in Example 109, except that piperidine was used instead of methylamine hydrochloride.
  • the target compound was obtained as a white solid (0.70 g, 20.0%) in the same manner as in Example 109, except that benzylamine was used instead of methylamine hydrochloride.
  • 1 H NMR (600 MHz, DMSO) ⁇ 7.33 (m, 5H), 4.35 (d, J 6 Hz, 2H) LCMS: 192.3 [M+H] +
  • the target compound was obtained as a white solid (1.97 g, 61.0%) in the same manner as in Example 109, except that 4-( N -acetylamino)aniline was used instead of methylamine hydrochloride.
  • the target compound was obtained as a white solid (0.42 g, 27.0%) in the same manner as in Example 109, except that pyrrolidine was used instead of methylamine hydrochloride.
  • the target compound was obtained as a white solid (1.74 g, 51.0%) in the same manner as in Example 109, except that 1-(pyridin-2-yl)piperazine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, D 2 O
  • the target compound was obtained as a white solid (1.27 g, 38.0%) in the same manner as in Example 109, except that 4-trifluoromethylaniline was used instead of methylamine hydrochloride.
  • 1 H NMR (600 MHz, DMSO) ⁇ 7.60 (q, J 8.4 Hz, 4H) LCMS: 246.0 [M+H] +
  • the target compound was obtained as a white solid (0.39 g, 12.0%) in the same manner as in Example 109, except that 4-chlorobenzylamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • LCMS 226.0 [M+H] +
  • the target compound was obtained as a white solid (0.17 g, 4.0%) in the same manner as in Example 109, except that N,N- dibenzylamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • LCMS 282.3 [M+H] +
  • the target compound was obtained as a white solid (0.28 g, 9.0%) in the same manner as in Example 109, except that 4-methoxybenzylamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • the target compound was obtained as a white solid (0.17 g, 6.0%) in the same manner as in Example 109, except that 4-fluorobenzylamine was used instead of methylamine hydrochloride.
  • 1 H NMR (600 MHz, DMSO) ⁇ 7.36 (m, 2H), 7.17 (m, 2H), 4.32 (d, J 6 Hz, 2H) LCMS: 210.0 [M+H] +
  • the target compound was obtained as a white solid (0.73 g, 30.0%) in the same manner as in Example 109, except that N,N- dihexylamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • 1.58 m, 4H
  • 1.29 m, 12H
  • the target compound was obtained as a white solid (0.71 g, 34.3%) in the same manner as in Example 109, except that N- methyl- N- butylamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • LCMS 172.1 [M+H] +
  • the target compound was obtained as a white solid (0.08 g, 5.0%) in the same manner as in Example 109, except that N- methyl- N- cyclohexylamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 2.46 m, 1H
  • 1.70 m, 2H
  • 1.53 m, 3H
  • 1.42 m, 2H
  • LCMS 198.1 [M+H] +
  • the target compound was obtained as a white solid (2.32 g, 70.0%) in the same manner as in Example 109, except that N,N- dicyclohexylamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • ⁇ 3.03 m, 2H
  • 1.96 m, 4H
  • 1.71 m, 4H
  • 1.57 m, 2H
  • 1.26 m, 8H
  • the target compound was obtained as a white solid (0.37 g, 13.0%) in the same manner as in Example 109, except that 4-chlorophenethylamine was used instead of methylamine hydrochloride.
  • the target compound was obtained as a white solid (0.15 g, 10.0%) in the same manner as in Example 109, except that 4-hydroxyphenethylamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • 3.38 s, 2H
  • 2.72 s, 2H
  • the target compound was obtained as a white solid (0.18 g, 8.0%) in the same manner as in Example 109, except that azepane was used instead of methylamine hydrochloride.
  • the target compound was obtained as a white solid (0.06 g, 15.0%) in the same manner as in Example 109, except that 4-trifluoromethoxyaniline was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • LCMS 262.1 [M+H] +
  • the target compound was obtained as a white solid (0.02 g, 6.0%) in the same manner as in Example 109, except that 4-trifluoromethylaniline was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO
  • 4.49 s, 2H
  • the target compound was obtained as a white solid (0.01 g, 6.0%) in the same manner as in Example 109, except that 4-trifluoromethoxybenzylamine was used instead of methylamine hydrochloride.
  • the target compound was obtained as a white solid (0.03 g, 40.0%) in the same manner as in Example 109, except that 2-(benzo[d][1,3]dioxol-5-yl)ethanamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 Hz, CD 3 OD
  • LCMS 250.1 [M+H] +
  • the target compound was obtained as a white solid (7.70 g, 22.0%) in the same manner as in Example 109, except that furan-2-ylmethanamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO-d 6 ) ⁇ 7.87 (m, 1H), 7.55 (s, 1H), 7.15 (m, 4H), 6.35 (m, 1H), 4.32 (s, 2H) LCMS: 182.0 [M+H] +
  • the target compound was obtained as a white solid (10.21 g, 35.0%) in the same manner as in Example 109, except that thiophenethylamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, DMSO-d 6 ) ⁇ 9.73 (s, 1H), 9.28 (s, 2H), 8.62 (s, 3H), 7.34 (m, 1H), 6.94 (m, 1H), 6.92 (m, 1H), 3.52 (s, 2H), 3.08 (s, 2H) LCMS: 212.0 [M+H] +
  • the target compound was obtained as a white solid (0.01 g, 12.2%) in the same manner as in Example 109, except that 2-fluoro-4-hydroxybenzylamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, CD 3 OD
  • LCMS 226.1 [M+H] +
  • the target compound was obtained as a white solid (0.01 g, 22.0%) in the same manner as in Example 109, except that 3-(4-fluorophenyl)propan-1-amine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, CD 3 OD
  • ⁇ 7.23 m, 2H
  • 7.01 m, 2H
  • 3.18 t, 2H
  • 2.68 t, 2H
  • the target compound was obtained as a white solid (0.09 g, 10.0%) in the same manner as in Example 109, except that 3-(4-methoxyphenyl)propan-1-amine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, CD 3 OD
  • ⁇ 7.14 d, 2H
  • 6.85 d, 2H
  • 3.18 s, 2H
  • 2.57 s, 2H
  • the target compound was obtained as a white solid (0.10 g, 33.0%) in the same manner as in Example 109, except that 2-iodobenzylamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, CD 3 OD
  • ⁇ 7.88 m, 1H
  • 7.43 s, 1H
  • 7.40 s, 1H
  • 7.06 s, 1H
  • 4.33 s, 2H
  • the target compound was obtained as a white solid (0.11 g, 25.5%) in the same manner as in Example 109, except that 3-iodobenzylamine was used instead of methylamine hydrochloride.
  • 1 H NMR 600 MHz, CD 3 OD
  • ⁇ 7.78 s, 1H
  • 7.67 s, 1H
  • 7.19 s, 1H
  • 7.18 s, 1H
  • 4.45 s, 2H
  • the target compound was obtained as a white solid (0.02 g, 11.0%) in the same manner as in Example 151, except that cyanoguanidine was used instead of piperidine cyanoguanidine.
  • 1 H NMR 600 MHz, CD 3 OD
  • ⁇ 2.51 m, 2H
  • 1.29 s, 6H
  • LCMS 184.2 [M+H] +
  • the target compound was obtained as a white solid (0.01 g, 6.0%) in the same manner as in Example 151, except that piperidine-1-carbamimidoyl cyanide and propan-1,3-diamine were used instead of piperidine cyanoguanidine and ethyl-3-amino-3-methylbutanoate hydrochloride.
  • 1 H NMR 600 MHz, CD 3 OD
  • LCMS 210.2 [M+H] +
  • the target compound was obtained as a white solid (0.01 g, 5.0%) in the same manner as in Example 151, except that ethyl-3-aminobutanoate hydrochloride was used instead of ethyl-3-amino-3-methylbutanoate hydrochloride.
  • 1 H NMR 600 MHz, CD 3 OD
  • 3.00 3.00
  • m, 1H 2.51
  • m, 2H 1.58
  • the target compound was obtained as a white solid (0.01 g, 5.0%) in the same manner as in Example 151, except that ethyl-3-amino-2-methylbutanoate hydrochloride was used instead of ethyl-3-amino-3-methylbutanoate hydrochloride.
  • the target compound was obtained as a white solid (0.04 g, 10.0%) in the same manner as in Example 151, except that ethyl-3-aminopropanoate hydrochloride was used instead of ethyl-3-amino-3-methylbutanoate hydrochloride.
  • the target compound was obtained as a white solid (0.12 g, 8.0%) in the same manner as in Example 151, except that ethyl-3-amino-3-cyclopropylpropanoate hydrochloride was used instead of ethyl-3-amino-3-methylbutanoate hydrochloride.
  • 1 H NMR (600 MHz, DMSO) ⁇ 3.73 (m, 1H), 3.48 (m, 4H), 2.76 (m, 1H), 2.43 (m, 1H), 1.68 (m, 6H), 1.52 (m, 1H), 0.90 (m, 4H)
  • LCMS 264.2 [M+H] +
  • the target compound was obtained as a white solid (0.01 g, 3.0%) in the same manner as in Example 151, except that piperidine-1-carbamimidoyl cyanide and 2-methylpropan-1,3-diamine were used instead of piperidine cyanoguanidine and ethyl-3-amino-3-methylbutanoate hydrochloride.
  • 1 H NMR 600 MHz, CD 3 OD
  • LCMS 224.2 [M+H] +
  • the target compound was obtained as a white solid (0.02 g, 3.0%) in the same manner as in Example 151, except that ethyl-3-amino-4-methylpentanoate hydrochloride was used instead of ethyl-3-amino-3-methylbutanoate hydrochloride.
  • the target compound was obtained as a white solid (0.02 g, 4.0%) in the same manner as in Example 151, except that cyanoguanidine and ethyl-3-amino-2-methylbutanoate hydrochloride were used instead of piperidine cyanoguanidine and ethyl-3-amino-3-methylbutanoate hydrochloride.
  • 1 H NMR 600 MHz, CD 3 OD
  • LCMS 170.2 [M+H] +
  • the target compound was obtained as a white solid (0.10 g, 8.0%) in the same manner as in Example 151, except that ethyl-3-amino-5-methylhexanoate hydrochloride was used instead of ethyl-3-amino-3-methylbutanoate hydrochloride.
  • the target compound was obtained as a white solid (0.01 g, 2.0%) in the same manner as in Example 151, except that piperidine-1-carbamimidoyl cyanide and butan-1,3-diamine were used instead of piperidine cyanoguanidine and ethyl-3-amino-3-methylbutanoate hydrochloride.
  • the target compound was obtained as a white solid (0.01 g, 2.0%) in the same manner as in Example 151, except that ethyl-3-aminohexanoate hydrochloride was used instead of ethyl-3-amino-3-methylbutanoate hydrochloride.
  • 1 H NMR 600 MHz, CD 3 OD
  • ⁇ 3.73 (m, 1H), 3.50 (m, 4H), 2.72 (m, 1H), 2.40 (m, 1H), 1.68 (m, 8H), 1.50 (m, 1H), 1.33 (m, 1H), 0.95 (m, 3H)
  • LCMS 266.2 [M+H] +
  • the target compound was obtained as a white solid (0.02 g, 4.0%) in the same manner as in Example 151, except that cyanoguanidine and ethyl-3-aminobutanoate hydrochloride were used instead of piperidine cyanoguanidine and ethyl-3-amino-3-methylbutanoate hydrochloride.
  • 1 H NMR 600 MHz, CD 3 OD
  • LCMS 170.1 [M+H] +
  • the target compound was obtained as a white solid (0.01 g, 5.0%) in the same manner as in Example 151, except that pentan-3,5-diamine was used instead of ethyl-3-amino-3-methylbutanoate hydrochloride.
  • 1 H NMR 600 MHz, CD 3 OD
  • LCMS 238.2 [M+H] +
  • HCT116 cells purchased from Korean Cell Line Bank (KCLB)
  • KCLB Korean Cell Line Bank
  • IC 50 cell growth inhibition concentration
  • HCT116 cells were placed in a 96-well plate and cultured in RPMI-1640 medium containing 10% calf serum for 16 hours until each well had a cell count of about 5000. Then, to obtain the IC 50 value of each compound, the 100 mM PBS stock compound was treated to the cell culture at concentrations of 10 mM, 1 mM, 200 ⁇ M, 40 ⁇ M, 8 ⁇ M, 1.6 ⁇ M, 0.32 ⁇ M, and 0.064 ⁇ M and then cultured for 48 hours; the 50 mM PBS, EtOH stock compound was treated to the cell culture at concentrations of 1 mM, 200 ⁇ M, 40 ⁇ M, 8 ⁇ M, 1.6 ⁇ M, 0.32 ⁇ M, and 0.064 ⁇ M and then cultured for 48 hours; and the 50 mM DMSO stock compound was treated to the cell culture at concentrations of 100 ⁇ M, 25 ⁇ M, 6.25 ⁇ M, 1.56 ⁇ M, 0.39 ⁇ M, 0.10 ⁇
  • OCR oxygen consumption rates
  • ECAR extracellular acidification rates
  • biguanide-based drugs exhibit an anticancer effect by inhibiting oxidative phosphorylation
  • the cellular metabolic actions such as oxygen consumption rates (OCR), extracellular acidification rates (ECAR), etc ., of the above compounds are measured.
  • A549 cell line (purchased from ATCC-American Type Culture Collection (ATCC)), a lung cancer cell line, is treated with the compounds and OCR and ECAR of the cells are measured and thereby those compounds which show an improved effect compared to phenformin are selected.
  • ATCC ATCC-American Type Culture Collection
  • the cells are plated on an XF96 cell culture plate containing RPMI1640 medium at a concentration of 5 ⁇ 10 3 cells and cultured in 37°C, 5% CO 2 conditions to allow them to be attached thereto.
  • the cells are treated with the drug at a concentration of 10 ⁇ M for 2 hours, the existing medium is washed with a medium for XF analysis (15 mM D-glucose, 15 mM sodium pyruvate, 4 mM L -glutamine, pH 7.4) to remove the medium using a Prep station and treated again with the drugs, and cultured in 37°C, non-CO 2 conditions in the Prep station for 1 hour. While culturing in the Prep station, a sensor cartridge is calibrated for 1 hour and added into a plate containing cells, and OCR and ECAR analyses are performed.
  • a medium for XF analysis 15 mM D-glucose, 15 mM sodium pyruvate, 4 mM L -glutamine, pH 7.4
  • the measured values of OCR and ECAR of the compounds are calculated with reference to the measured values of OCR and ECAR of the control group which is set at 0% and the values of OCR and ECAR of phenformin, which was used as the reference drug, set at 100%, and those compounds which show an improved effect compared to those of phenformin are selected. From the primarily-selected compounds, those compounds which show an improved effect are treated at various concentrations (0 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, and 20 ⁇ M) and their reactivity according to concentration was obtained.

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WO2022106505A1 (fr) 2020-11-18 2022-05-27 Institut Curie Dimères de biguanidines et leurs utilisations thérapeutiques

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KR20180087189A (ko) * 2017-01-24 2018-08-01 연세대학교 산학협력단 염증성 질환, 자가면역 질환, 또는 이들의 조합을 예방 또는 치료하기 위한 약학적 조성물 및 이를 이용한 방법
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WO2019233982A1 (fr) 2018-06-05 2019-12-12 Institut Curie Composés à radical biguanidyle et leurs utilisations
WO2022106505A1 (fr) 2020-11-18 2022-05-27 Institut Curie Dimères de biguanidines et leurs utilisations thérapeutiques

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